The ubiquitin/proteasome pathway (UPP) plays a central role in the selective degradation of intracellular[unreadable] proteins. The translational research that we propose addresses UPP-regulated mechanisms that can be[unreadable] manipulated to increase neuroprotection and/or neuronal recovery following CNS injuries. There is an[unreadable] obvious gap in the knowledge of these UPP-regulated mechanisms. The main goal of this application is to[unreadable] characterize molecular mechanisms regulated by the UPP that are neuroprotective and promote neurite[unreadable] outgrowth following CNS injury. To characterize these UPP-regulated pathways, two of the UPP steps will be[unreadable] manipulated: (1) Proteasorne activity by pharmacological and more specific genetic approaches and[unreadable] (2) Ubiquitination by overexpressing a ubiquitin ligase that promotes neurite outgrowth. The effect of these[unreadable] UPP manipulations will be investigated in human neuroblastoma SK-N-SH cells as well as in rat dorsal root[unreadable] ganglion and cortical neurons grown in the presence of axonal regeneration inhibitors. Through molecular,[unreadable] biochemicaland immunocytochemical analyses we will assess the effects of the UPP-manipulations on the[unreadable] Rho family of small GTPases, on the putrescine-producing enzyme ornithine decarboxylase (ODC), and on[unreadable] the expression of the neuron-specific ubiquitin hydrolase, UCH-L1. Our working hypothesis is that the UPP-manipulations[unreadable] will (1) affect the levels of Rho proteins, which will in turn enhance neurite outgrowth, as Rho[unreadable] proteins are key players in preventing CNS neurite outgrowth and axonal regeneration, (2) enhance ODC[unreadable] levels causing a rise in putrescine, which in turn will block the effect of myelin inhibitors on neurite outgrowth,[unreadable] and (3) alter the levels of UCH-L1, which facilitates the use and reuse of ubiquitin molecules, a process that[unreadable] will regulate the turnover of proteins relevant to CNS neurite outgrowth and axonal regeneration. This project[unreadable] draws on the unique combination of skills and expertise of our groups on the UPP (Figueiredo-Pereira) and[unreadable] axonal regeneration (Filbin). We expect our results to be applicable to treatment-of neurological conditions[unreadable] that involve neuronal damage, such as stroke, neurodegenerative disorders and spinal cord injury.[unreadable] Relevance to Public Health: Our research addresses mechanisms that can be manipulated to increase[unreadable] neuroprotection and/or neuronal recovery following neurological conditions such as stroke, spinal cord injury![unreadable] and Alzheimer's disease. It is particularly relevant to health disparities as, for example, African-Americans:[unreadable] and Hispanics of both genders have a higher death rate due to stroke than White Americans. The aging:[unreadable] population of African-Americans and Hispanics presents a particular challenge, as older adults who havei[unreadable] had a stroke have a higher risk of developing neurodegenerative disorders such as Alzheimer's disease.[unreadable] expect that our translational research will identify new targets for effectively treating CNS injury.